The background descriptions provided throughout are for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
The estimated revenues for the U.S. Tissue Engineering Market in 2000 are $230 million with a growth rate of 20 percent. Revenues will be led by bone regeneration products (48.5 percent of revenues), followed by skin engineering products (36.8 percent of revenues) and cartilage repair products (14.7 percent of revenues). Breast reconstruction typically is performed to re-create one or both breasts after a single or double mastectomy.
Fibrin scaffolds are highly porous, protein-based hydrogels frequently used in regenerative medicine as a substrate for cells and for encapsulation of proteins such as growth factors (GFs) (Shaikh et al. 2008; Dehghani and Annabi 2011; Seliktar 2012). Similar to other hydrogels, the release of a bioactive molecule (i.e., payload) from a conventional fibrin scaffold as well as degradation of the scaffold are dominated by processes such as molecular diffusion, material degradation, and cell migration. Thus the rate that biochemical (e.g., GFs) or mechanical (e.g., microporosity) cues are presented in a conventional fibrin scaffold cannot be externally controlled spatially or temporally, especially after the scaffold is implanted in vivo. It is well documented that spatial and temporal patterns of GF signaling are critically important in regenerative processes (Bos et al. 2001; Sojo et al. 2005); additionally, cellular processes are influenced by the mechanical properties of the local scaffold microenvironment (Metallo et al. 2007; Tse et al. 2012; Barthes et al. 2014; Fujie et al. 2014; Satyam et al. 2014). Alternatively, scaffolds have been designed to respond to environmental or externally applied stimuli—such as light, electricity, magnetic fields, temperature, enzymes, and pH—in order to obtain spatiotemporal control of payload release or to modify scaffold architecture after implantation (Sakiyama-Elbert and Hubbell 2000b; Sakiyama-Elbert and Hubbell 2000a; Matsusaki and Akashi 2005; Thornton et al. 2005; Frimpong et al. 2007; Kulkarni and Biswanath 2007; Lavigne et al. 2007; Wu et al. 2008; Zhao et al. 2011). Despite their promising potential in controlling both biochemical and mechanical cues, further development of responsive scaffolds is limited in part by the clinical translatability of the modulating stimulus, especially in terms of focusing the stimulus or targeting deeply located scaffolds.
Ultrasound (US) has been explored as a stimulus for achieving spatial and temporal control with responsive scaffolds due to its potential for translatability. Unlike other stimuli, US can be applied non-invasively, focused with submillimeter precision, and penetrate deep within the body. Broadly, US can be used to generate mechanical and/or thermal effects within a scaffold to achieve on-demand control. In many instances, US-responsive scaffolds contain sonosensitive particles such as emulsions or microbubbles, thus making the scaffold more responsive to US (Epstein-Barash et al. 2010; Fabiilli et al. 2013). However, it has been demonstrated using low frequency US that payload release can be modulated from scaffolds in the absence of sonosensitive particles (Huebsch et al. 2014). Sonosensitive particles are usually administered intravascularly for US-based imaging or therapy, with microbubbles used clinically as US contrast agents. These particles are typically micron-size in diameter, contain a perfluorocarbon (PFC) dispersed (i.e., core) phase, and are stabilized by a surfactant shell. Microbubbles, which contain a gaseous PFC core, have been used to indirectly facilitate payload delivery from an in situ cross-linking hydrogel containing liposomes co-encapsulated with the microbubbles (Epstein-Barash et al. 2010). In the absence of US, microbubbles have also been used to create on-demand, microporous agarose hydrogels (Lima et al. 2012) or to simultaneously act as a porogen and GF carrier within poly(lactic-co-glycolic-acid) scaffolds (Nair et al. 2010).